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Management and prevention strategies for respiratory syncytial virus (RSV) bronchiolitis in infants and young children: a review of evidence-based practice interventions.

Respiratory syncytial virus (RSV), first isolated more than 40 years ago, is the most common pathogen of bronchiolitis and pneumonia among infants and children under 2 years of age (Hall, 2001; Panitch, 2001; Sorrentino, Powers, & The Palivizumab Outcomes Study Group, 2000). RSV infection commonly causes mild cold-like symptoms in older children and adults. However, in infants and toddlers RSV can cause more serious lower respiratory tract infection (LRTI), especially in premature infants with chronic lung or heart disease or those who are immunocompromised (Centers for Disease Control and Prevention [CDC], 2002). RSV infection has a substantial social impact, both in economic terms and human suffering (i.e. loss of work and wages, hospitalization, pulmonary sequela, or death of a child). Each year in the United States alone, it is estimated that 0.5% to 2% of infants and young children with RSV infection require hospitalization with an associated cost of $300 million (CDC, 2001). Unfortunately, there is a lack of consensus regarding the optimal treatment for children with RSV infection.

Epidemiology

Approximately 80% of infants are infected with RSV during the first year of life with a peak incidence between 2-6 months of life. Nearly 100% have been infected by the age of 2 years (Agency for Healthcare Research and Quality [AHRQ], 2003; Gadomski, 2002; Meissner et al., 1999). In the northern hemisphere, RSV occurs in epidemics that tend to last 5 months, beginning in the fall between late October through mid-December, and lasting through early spring. In tropical climates, the pattern is less predictable, occurring more during the rainy periods (CDC, 2002; McIntosh, 2000).

Although most RSV infections are usually mild to moderate in severity and can be treated on an outpatient basis, each year RSV is responsible for approximately 125,000 pediatric hospitalizations, with a mortality rate of about 2% (Panitch, 2001). In infants with chronic lung or heart disease, the RSV mortality rate may be as high as 5% (Shay et al., 1999).

RSV infection is more common in infants who are not breast fed, live in crowded conditions, attend daycare, and live with mother's who smoke cigarettes and are socially disadvantaged (Orenstein, 2000). Reinfection is also common because RSV antibodies do not provide long-lasting immunity. However, the clinical severity of subsequent infections is usually less severe than that of initial infection (Levy & Graber, 1997). Anti-RSV antibodies transmitted via the placenta are partially protective during the first 6 weeks of life in full-term infants. Premature infants often lack sufficient maternal antibodies for protection and are, therefore, more susceptible to RSV infection early in life.

Etiology and Pathophysiology

RSV is a member of the paramyxovirus family containing a single strand RNA and is related to the parainfluenza, mumps, and measles virus. The two major strains of RSV are A and B. The A strain is responsible for the majority of more severe forms of RSV bronchiolitis (Martinello, Chen, Weibel, & Kahn, 2002; Walsh, McConnochie, Long, & Hall, 1997). In a recent study by Martinello et al. (2002), the investigators found a subgroup of the A strain (GA3) was associated with more severe disease. The different strains of RSV often circulate at the same time, and season-to-season variation is found in the predominant strain (American Academy of Pediatrics [AAP], 2003; Martinello et al., 2002).

RSV invades the bronchiolar epithelial cells causing inflammation and edema. The membranes of the infected cells fuse with adjacent cells to form a large, multinucleated cell creating large masses of cells or "syncytia" (McIntosh, 2000; Wong et al., 2003). The bronchiole mucosa ultimately begins to swell, and the lumina fill with mucus and exudate. Inflammatory cells infiltrate the area resulting in the shedding of dead epithelial cells, which causes obstruction of small airway passages resulting in hyperinflation and areas of atelectasis (Linzer & Guthrie, 2003). Bronchiole passages normally dilate on inspiration, allowing for adequate air intake, but narrow on expiration. The inflammation and exudate caused by the RSV infection results in bronchiole obstruction during expiration, air trapping, poor exchange of gases, increased work of breathing, and a characteristic expiratory wheeze (Sandritter & Kraus, 1997; Wong et al., 2003).

A strong association has been suggested between severe RSV infection in infancy and long-term pulmonary sequela. Multiple studies have suggested that RSV infection during infancy is an important contributory factor to wheezing and additional lower respiratory tract problems in childhood (Eriksson, Bennet, & Nilsson, 2000; McBride, 1999; Openshaw & Hewitt, 2000; Sigurs, Bjarnason, Sigurbergsson, & Kjellman, 2000). In the study by Sigurs et al. (2000), the authors found a high association between hospitalized infants with bronchiolitis and the development of asthma. The study followed 140 children till age 7 1/2 years and found 30% of the children developed asthma verses 2% in the control subjects. A literature review by McBride (1999) on the association between RSV bronchiolitis and asthma found evidence to suggest either viral illness causes damage to the infant's lung or is an indicator of preexisting susceptibility to long-term respiratory abnormality later in life.

Transmission

RSV is highly contagious and is transmitted through direct contact with respiratory secretions and indirect inoculation from contaminated surfaces. RSV can live on countertops for 30 hours and on clothes or hands for less than 1 hour (CDC, 2001; Linzer & Guthrie, 2003). Such sustainability enables the virus to spread easily in households and daycare centers (CDC, 2001). Children who attend daycare, live in crowded conditions, live with a family member who smokes, have a chronic illness, or were born premature are at highest risk for the development of RSV infection (Linzer & Guthrie, 2003). Preventive measures include frequent handwashing, avoiding contact with adults and children with symptoms of upper respiratory infections (URI), and preventing sick children from attending daycare or school until URI symptoms have resolved. Prophylaxis with palivizumab and intravenous RSV immune globulin for high risk infants should be considered (AAP, 2003).

Clinical Manifestations

The clinical presentation of RSV bronchiolitis is variable depending on the severity of the infection and the age and condition of the infant or child. The symptoms begin 3-5 days after inoculation with the virus and the mean duration is 12 days (Swingler, Hussey, & Zwarenstein, 2000). The symptoms of mild infection include rhinorrhea, mild cough, irritability, and low-grade fever for 1-3 days. Moderate infections and infections in infants and young children often present with more pronounced cough, wheezing, moderate fevers to 102[degrees]F, and decreased feeding. As the condition progresses and the infant has to work harder to breath, nasal flaring, grunting, tachypnea, and retractions develop. If the infant does not receive supportive therapy or the RSV infection is severe, the infant will become listless, hypoxic with diminished breath sounds, may experience apnea spells, and can rapidly progress to cyanosis and respiratory failure (Wong et al., 2003) (see Table 1).

Risk Factors For Severe RSV Infection

Prematurely born infants represent the largest population at risk for severe complications of RSV infection. Premature infants have a 10-fold higher risk of RSV-related hospitalization than do full-term infants (Boyce et al., 2000). They are born before sufficient passage of maternal immunoglobulin G (IgG) antibodies, resulting in inadequate immunity to prevent RSV infection during the early months of life. In addition, they have smaller airways, which can more easily become obstructed by edema and necrotic debris resulting in poor gas exchange and increased respiratory effort (Greenough, 2001). Premature infants have less energy reserve than full-term infants and, therefore, can progress to respiratory failure more quickly. Children with complicated congenital heart disease, underlying lung disease (e.g., bronchopulmonary dysplagia, chronic lung disease, and cystic fibrosis), or immunosuppression (e.g., chemotherapy, congenital immunodeficiencies, and children with transplants) are also high risk for more severe RSV infection (Linzer & Guthrie, 2003).

Diagnosis

The diagnosis of bronchiolitis is made by history and physical examination. Diagnostic criteria include exposure to persons with URI symptoms, a prodromal phase of URI symptoms followed by wheezing occurring during the winter months (AHRQ, 2003; Children's Hospital Medical Center [CHMC], 2001). Differential diagnoses include asthma, pneumonia, cystic fibrosis, heart failure, foreign body aspiration, pertussis, and tumor (Orenstein, 2000). In infants and children with moderate or severe respiratory symptoms, a chest x-ray is often ordered to rule out other respiratory conditions. Radiographic examination findings of bronchiolitis reveal hyperinflation, patchy atelectasis, and peribronchial wall thickening and can usually differentiate between pneumonia and bronchiolitis. Definitive diagnosis of RSV as the causative agent for bronchiolitis is accomplished by enzyme-linked immunosorbent assay (ELISA) that detects antigens. A nasal washing specimen is obtained and has a sensitivity ranging from 80%-90% (AHRQ, 2003). However, according to the AHRQ (2003), routine laboratory screenings such as RSV assays, complete blood counts (CBCs), and chest x-rays provide little additional information above and beyond a thorough history and physical examination in the diagnosis of RSV bronchiolitis.

Management

Controversy surrounds the treatment of RSV bronchiolitis. Management of RSV bronchiolitis in infants and young children is predominantly by supportive care measures (AHRQ, 2003; Greenough, 2001). Treatment of bronchiolitis includes maintenance of adequate fluid, sufficient caloric intake to meet the increased basal metabolic needs associated with a respiratory illness, rest, the use of nasal saline drops and suction to promote ease of breathing, and the use of antipyretics/mild analgesics to control fever and minimize irritability associated with discomfort. Most infants and young children with bronchiolitis can be treated at home. Assessment of respiratory status and infant fatigue is critical. Pulse oximeter readings should be taken on all infants and children with symptoms of increased respiratory effort. Close follow up is important and careful instructions should be given to the parents and documented in the record regarding (a) signs of increasing respiratory distress, (b) signs of dehydration, (c) guidelines for oral intake, (d) fever management and antipyretic use, and (e) how to access health care services if symptoms worsen (Goodman & Brady, 2000).

Hospitalization is required for infants and children with tachypnea >70, marked retractions, lethargy, or a history of poor fluid intake. The degree of medical intervention is usually determined by the child's level of oxygenation as indicated by pulse oximetry and/or arterial blood gases (Rodriguez, 1999; Wang et al., 2003). Humidified mist therapy is usually combined with oxygen by hood, tent, isolette, or nasal prongs in concentrations sufficient to alleviate dyspnea and hypoxia. Clinicians must carefully monitor signs of impending respiratory failure, such as the inability to maintain adequate oxygen saturations or rising arterial carbon dioxide levels. Ventilatory assistance (i.e., intubation) should be considered for infants with recurrent apnea or severe oxygen desaturation (Gadomski, 2002). Adequate hydration is also important, however, oral fluid intake may be contraindicated because of tachypnea, weakness, and/or fatigue. Parenteral fluids are usually provided in the hospitalized infant until the acute stage of the disease has passed (Rodriguez, 1999; Wang et al., 2003).

Pharmacotherapy

Multiple medications with various mechanisms of action have been used in the treatment of children with RSV infection. These medications include bronchodilators, corticosteroids, and antivirals (AHRQ, 2003).

Bronchodilators. Since bronchiolitis and asthma present with similar symptoms, Beta 2-agonists (i.e., albuterol) have been used with little data to support their use. A review by Kellner, Ohlsson, Gadomski, & Wang (2003) showed that bronchodilators had short-term positive effects on respiratory status but did not alter hospitalization rates. Flares and Horwitz (1997) found no improvement in oxygenation or reduction in hospitalization rates with the use of albuterol.

Racemic epinephrine. Menon, Sutcliffe, and Klassen (1995) found racemic epinephrine, which has both [alpha]-adrenergic and [beta]-adrenergic activity, was better than albuterol in reducing hospitalization of infants age 6 weeks to 1 year with bronchiolitis presenting to the ER. They found that only 30% of the 21 infants treated with racemic epinephrine required hospitalization as compared to 75% of the 2l infants treated with albuterol. The total number in this study was too small to recommend this treatment modality without further study. Patel, Platt, Pekeles, and Ducharme (2002) randomized 149 hospitalized infants with bronchiolitis into three treatments groups; 50 receive racemic epinephrine, 51 received nebulized albuterol, and 48 received a placebo. The authors found no difference in the effectiveness of therapy for infants hospitalized with bronchiolitis.

Corticosteroids. Research has shown that corticosteroids, systemic or inhaled, do not seem to exhibit the same beneficial respiratory effects in infants with RSV bronchiolitis as they do in children with severe asthma and, thus, are not recommended (AAP, 2003; AHRQ, 2003; Cade et al., 2000; CHMC, 2001; De Boeck, Van der Aa, Van Lierde, Corbeel, & Eeckels, 1997; Roosevelt et al., 1996). A meta-analysis by Garrison et al. (2000) found infants receiving Corticosteroids had a reduction in length of stay of 0.43 days compared to the placebo treatment. However, several studies were excluded and upon further analysis there was found to be no difference in length of stay (CHMC, 2001).

The AHRQ (2003) recommends additional, large, well-designed studies be conducted before evidence-based recommendations can be made for the use of albuterol, racemic epinephrine, or corticosteroids in the management of RSV infections.

Antivirals. Ribavirin. Aerosolized ribavirin is the only specific antiviral drug that is licensed for the treatment of RSV infection of infants and young children in the United States (AHRQ, 2003). Because ribavirin acts to inhibit viral replication, the earlier it is used in the course of acute RSV infection, the greater the likelihood it will be beneficial (Rodriguez, 1999). One recent study found the use of ribavirin early in the course of RSV infection in previously healthy infants reduced both the incidence and severity of recurrent wheezing episodes later in life (Edell, Khoshoo, Ross, & Salter, 2002). But other studies have not found ribavirin therapy to reduce either mortality rates or duration of mechanical ventilation (Everard, Swarbrick, Rigby, & Milner, 2001; Guerguerian, Gauthier, Lebel, Farrell, & Lacroix, 1999; Moler, Steinhart, Ohmit, & Stidham, 1996). Thus, ribavirin appears to have limited clinical efficacy in previously healthy infants with severe RSV infection.

Prevention

Currently, there are two methods of preventing RSV infection in infants and children that are at an increased risk for developing a severe infection. RSV-IGIV (RespiGam, Massachusetts Public Health Biologic Laboratories, and Medimmune, Inc, Gaithersburg, MD) was approved for use by the FDA in 1996 for the prevention of severe RSV infection in those children less than 24 months of age with chronic lung disease or premature birth (35 weeks gestation) (AAP, 1998). RSV-IGIV was the first agent clinically approved for the prophylaxis of severe RSV infections. RSV-IGIV consists mostly of immunoglobulin G and trace amounts of immunoglobulin A and M (Sandritter & Kraus, 1997). In one of the larger studies conducted by the PREVENT Study Group children 24 months of age with chronic lung disease and/or 35 weeks gestational age received a monthly infusions of RSV-IGIV (750 mg/kg/dose). The study found a 41% reduction in hospitalization rates, a 53% decrease in days of hospitalization due to RSV, and a 60% decrease in the number of days requiring supplemental oxygen (The PREVENT Study Group, 1997). RSV-IGIV should not be administered to those children with chronic heart disease due to the fact that efficacy has not been established in this patient population. RSV-IGIV is not recommended for administration in children that have had a previously severe adverse reaction associated with human immunoglobulin products or in children with immunoglobulin A deficiency because of the possibility of anaphylaxis (Sandritter & Kraus, 1997). Monthly intravenous prophylaxis is also relatively expensive and time consuming (AAP, 1998).

In 1998, palivizumab (Synagis7; MedImmune Inc., Gaithersburg, MD), a humanized RSV neutralizing monoclonal antibody, received FDA approval for the prevention of LRTI in infants at high risk for developing severe RSV disease (Sorrentino et al., 2000). As part of the impact-RSV trial, it was found that palivizumab reduced RSV hospitalizations by 55% for all children enrolled, by 39% for children with chronic lung disease, and by 80% for children with a history of prematurity without chronic lung disease (Impact-RSV Study Group, 1998; Sorrentino et al., 2000). Synagis is not a human blood product and, therefore, does not have the risks associated with blood products, as does RSV-IGIV. Synagis is also easier to administer than RSV-IGIV (1 intramuscular injection/month vs. 4-hour intravenous infusion), and it can be administered in an outpatient setting (AAP, 1998).

The most important aspect of RSV prevention is education. It is necessary for both parents and caregivers of infants to be informed of the importance of reducing exposure and transmission of the disease, especially when the infant is high risk. The most important method for reducing the transmission of RSV, as well as other infectious diseases, is frequent and consistent handwashing, especially when caring for children who are high risk for severe RSV infection (AAP, 1998). Additional preventative measures include eliminating cigarette smoke from the child's environment and limiting exposure to crowds and other children (e.g., day care).

Summary

RSV Bronchiolitis is a common pediatric illness, affecting almost 100% of children < 2 years of age. Based on the review of studies, evidence suggests the mainstay of treatment is supportive and symptomatic management. According to AHRQ, at present, "evidence is insufficient to recommend any of the treatments studied over good supportive care of affected infants and children" (2003, pg. 5), Prevention of severe RSV infection in young children with RSV-IG or Synagis has proven successful in clinical outcomes. However, their widespread usage is prohibitive due to the expensive cost of each month]y dose. Thus, only high-risk infants receive the benefits of prophylactic treatment.

Development of a RSV vaccine has been difficult; previously developed vaccines, which used inactivated whole virus, triggered disease in infants. Until recently it was not known how these viruses could evade or even alter immune responses. With enhanced understanding of how the virus affects the immune system, improvements can be made in the development of long-term preventative vaccines. The ultimate treatment goal of reducing disease severity and/or preventing infection and decreasing the length of hospitalization will serve to lessen morbidity and mortality rates, as well as hospitalization costs, and ultimately improve the quality of life in young children.
Table 1. Symptoms of RSV

     Mild              Moderate              Severe

Cough             Irritability         Wheezing
Rhinitis          Tachypnea            Rales
Low grade fever   Increased wheezing   Marked retractions
Wheezing          Increased cough      Nasal flaring
Tachypnea         Retractions          Grunting
Decreased PO                           Tachypnea > 70
 intake                                Cyanosis
Vomiting                               Decreased breath
Diarrhea                                sounds
                                       Listlessness
                                       Hypoxia
                                       Apnea
                                       Respiratory failure


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Wong, D.L., Hockenberry, M.J., Wilson, D., Winkelstein, M.L., & Kline, N.E. (2003). Respiratory syncytial virus (RSV)/bronchiolitis. In Nursing care of infants and children (7th ed., pp. 1366-1368). St. Louis, MO: Mosby, Inc.

Allison C. Cooper, MSN, RN, PNP, is a recent graduate, Yale University School of Nursing, New Haven, CT.

Nancy Cantey Banasiak, MSN, PNP, APRN, BC, is Assistant Professor, Pediatric Nurse Practitioner Specialty, Yale University School of Nursing, New Haven CT.

Patricia Jackson Allen, MS, PNP, FAAN, is Lecturer, Pediatric Nurse Practitioner Specialty, Yale University School of Nursing, New Haven, CT.
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Title Annotation:Primary Care Approaches
Author:Cooper, Allison C.; Banasiak, Nancy Cantey; Allen, Patricia Jackson
Publication:Pediatric Nursing
Date:Nov 1, 2003
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